title: Near-infrared pH-activatable fluorescent probes for imaging primary and metastatic breast tumors.
abstract: Highly tumor selective near-infrared (NIR) pH-activatable probe was developed by conjugating pH-sensitive cyanine dye to a cyclic arginine-glycine-aspartic acid (cRGD) peptide targeting α(v)β(3) integrin (ABIR), a protein that is highly overexpressed in endothelial cells during tumor angiogenesis. The NIR pH-sensitive dye used to construct the probe exhibits high spectral sensitivity with pH changes. It has negligible fluorescence above pH 6 but becomes highly fluorescent below pH 5, with a pK(a) of 4.7. This probe is ideal for imaging acidic cell organelles such as tumor lysosomes or late endosomes. Cell microscopy data demonstrate that binding of the cRGD probe to ABIR facilitated the endocytosis-mediated lysosomal accumulation and subsequent fluorescence enhancement of the NIR pH-activatable dye in tumor cells (MDA-MB-435 and 4T1/luc). A similar fluorescence enhancement mechanism was observed in vivo, where the tumors were evident within 4 h post injection. Moreover, lung metastases were also visualized in an orthotopic tumor mouse model using this probe, which was further confirmed by histologic analysis. These results demonstrate the potential of using the new integrin-targeted pH-sensitive probe for the detection of primary and metastatic cancer.
authors.affiliation: Department of Radiology, Washington University , St. Louis, Missouri 63110, United States.
authors.forename: Hyeran
authors.initials: H
authors.lastname: Lee
authors.forename: Walter
authors.initials: W
authors.lastname: Akers
authors.forename: Kumar
authors.initials: K
authors.lastname: Bhushan
authors.forename: Sharon
authors.initials: S
authors.lastname: Bloch
authors.forename: Gail
authors.initials: G
authors.lastname: Sudlow
authors.forename: Rui
authors.initials: R
authors.lastname: Tang
authors.forename: Samuel
authors.initials: S
authors.lastname: Achilefu
mesh_terms: D001943:Breast Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000556:secondary; D003952:Diagnostic Imaging; D042783:Endothelial Cells / Q000378:metabolism; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D039302:Integrin alphaVbeta3 / Q000032:analysis / Q000096:biosynthesis; D018613:Microscopy, Confocal; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics; D012680:Sensitivity and Specificity; D019265:Spectroscopy, Near-Infrared; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
chemical_list: D005456:Fluorescent Dyes; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide